The proposed project will investigate the neuroadaptive and synaptic changes associated with drug addiction within the cholinergic neuronal network system. Our recent findings examined the role of a specific subpopulation of striatal neurons in the rat, called cholinergic interneurons, in cocaine reinforcement. These cells are activated (in a dose-dependent manner) following the acute self-administration of cocaine in the shell compartment of the nucleus accumbens and in the ventromedial quadrant of the dorsal striatum (two targets of the mesolimbic dopamine pathway). In addition, these cells possess dopamine receptors that enable them to respond to cocaine-induced dopamine changes. These recent findings implicate these cholinergic interneurons as potential key targets of drug addiction. Two specific aims are proposed: 1) To quantify changes in dopamine D5 (a D1-type receptor) and D2 receptor expression at the light microscopic level following chronic (2 weeks) self-administration of cocaine and following withdrawal (2 weeks) from cocaine. Although this experiment has not been performed specifically in the cholinergic interneurons, previous findings suggests that we should find a global increase in dopamine D1-type receptors following chronic treatment with cocaine (Self and Nestler 1995; Koob, 1996) and a global increase in dopamine D2 receptors following withdrawal in the striatum (Sousa et al., 1999); and 2) To quantify synapses onto cholinergic interneurons and synapses by these neurons onto striatal neurons at the electron microscopic level following chronic self-administration and withdrawal from cocaine. The uniqueness of this proposal lies in the ability of the sponsor's laboratory to look at drug changes at the microcircuit level with respect to a specific cell population in an area of the brain that is key to addiction. This is the only lab to have linked cholinergic interneurons anatomically to addiction using Fos. Moreover, we are investigating these changes with respect to the cholinergic system in an attempt to identify functionally relevant changes in the system that may explain relapse, craving, and other drug-related phenomena. These findings may help to develop a more effective treatment for those that suffer from drug addiction by identifying a specific microcircuit of the brain to target at a particular stage of addiction.